Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term ‘fatty liver hepatitis’ first appeared in 1962, it was in 1980 that the term ‘non-alcoholic steatohepatitis’ (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.
- fatty liver
- molecular pathology
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Correction notice This article has been corrected since it published Online First. The second author affiliation has been amended and the funding and competing interests statements added.
Contributors Concept and supervision: AG and MT; acquisition of data: AG, DT, HD and MT; analysis and interpretation of data: AG, DT, HD and MT; drafting of the manuscript: AG and MT; critical revision of the manuscript for important intellectual content: AG, DT, HD and MT; obtained funding: AG, DT and MT; material support: AG, DT and HD.
Funding This work has been supported by the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project. The LITMUS project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no 777377. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.
Competing interests AG has declared receiving grants from Intercept, Novartis, Exalenz, Falk and Kibion and has received personal fees from Intercept, Novartis, Gilead, Pfizer, Falk, MSD, BMS, Ipsen, Sanofi-Aventis,Bayer, Eisai, CSL Behring, Sequana, Merz, Abbvie and Alexion. DT reports consultation fees from Intercept Pharmaceuticals Inc, Allergan plc, Cirius Therapeutics Inc, Alimentiv Inc, Clinnovate Health UK Ltd and an educational grant from Histoindex Pte. MT has received research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda and travel grants from Abbvie, Falk, Gilead and Intercept. He further has advised for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, Jannsen, MSD, Novartis, Phenex, Regulus and Shire and has served as speaker for Falk Foundation, Gilead, Intercept and MSD. He is also co-inventor of patents on the medical use of NorUDCA filed by the Medical Universities of Graz and Vienna.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.